1. Field of Invention
The current invention concerns novel analogs of 1.alpha.,25-dihydroxyvitamin D.sub.3 which are agonists for both the slow genomic responses and agonists of rapid nongenomic responses and analogs which act solely as agonists or antagonists for the rapid nongenomic cellular responses in a wide array of diseases in which 1.alpha.,25-dihydroxyvitamin D.sub.3 or its prodrugs are involved. In particular, the invention concerns analogs depicted by the general formulae I-V.
2. Background Art and Related Art Disclosures
Vitamin D.sub.3 is a secosteroid which is responsible for a wide variety of biological responses in higher animals. These biologicals include maintenance of calcium homeostasis, immunomodulation and selected cell differentiation. Vitamin D.sub.3, itself, is biologically inert. However, metabolism of vitamin D.sub.3 first to 25-dihydroxyvitamin D.sub.3 and then to such metabolites as 1.alpha.,25-dihydroxyvitamin D.sub.3 [1.alpha.,25(OH).sub.2 D.sub.3 ] results in the formation of biologically active compounds which are responsible for the wide array of biological responses which are observed as part of the vitamin D endocrine system.
A great number of normal physiological functions depends on vitamin D metabolism. Its deficiencies and/or overproduction can result in severe disbalance of homeostasis and in diseases of bone, the immune system, kidney, liver, brain, skin and other organs. Overproduction of 25(OH)D.sub.3 or 1.alpha.,25(OH).sub.2 D.sub.3 produces toxicity and hypercalcemia. Both these disbalances have very serious impact on the well-being and health of the individual.
It would, therefore, be advantageous to have available substitute compounds able to act in the same way as 1.alpha.,25(OH).sub.2 D.sub.3 but lacking the undesirable secondary symptoms.
1.alpha.,25(OH).sub.2 D.sub.3 generates many biological genomic responses by interaction with nuclear receptors. These responses which result in gene expression of the appropriate protein are slow, typically occurring within several hours to several days. The result of this interaction with nuclear receptors is the regulation of gene transcription (Crit. Rev. Eukar. Gene Exp., 2:65-109 (1992), Annu. Rev. Nutr., 11:189-216 (1991), Vitamin D: Gene Regulation, Structure-Function Analysis and Clinical Application, (Norman, A. W., Bouillon, R., and Thomasset, M., Eds.) pp. 146-154, Walter de Gruyter, Berlin (1991)). The nuclear receptor for 1.alpha.,25(OH).sub.2 D.sub.3 has been shown to be present in 30 different tissues and it belongs to the same family of proteins which includes receptors for the steroid hormones, and retinoic acid and thyroxine (Crit. Rev. Eukar. Gene Exp., 2:65-109 (1992), FASEB J., 2:3043-3053 (1988), Endocr. Rev., 3:331-366 (1982)).
In addition to slow genomic responses, a subset of biological responses mediated by 1.alpha.,25((OH).sub.2 D.sub.3 occur via a rapid nongenomic mechanism which was recently discovered (Vitamin D: Gene Regulation, Structure-Function Analysis and Clinical Application, (Norman, A. W., Bouillon, R., and Thomasset, M., Eds.) pp. 146-154, Walter de Gruyter, Berlin (1991) and Endocrinology, 115:1476-1483 (1984)). These rapid nongenomic responses include the rapid hormonal stimulation of intestinal Ca.sup.2+ transport known as transcaltachia (Endocrinology, 118:2300-2304 (1986), J. Steroid Biochem, 25:905-909 (1986) and Biochem. Biophys. Res. Commun., 166:217-222 (1990) which involves the opening of Ca.sup.2+ channels as described in J. Biol. Chem., 264:20265-20274 (1989). Other rapid nongenomic cellular responses which are mediated by 1.alpha.,25((OH).sub.2 D.sub.3 include opening of voltage-gated Ca.sup.2+ channels in rat osteosarcoma cells (Endocrinology, 127:2253-2262 (1990), Am. J. Physiol., 249:F117-F123 (1985)) as well as other rapid effects in kidney (FEBS Lett., 259:205-208 (1989)), liver (Endocrinology, 127:2738-2743 (1990)), parathyroid cells (J. Biol. Chem., 264:20403-20406 (1989)) and intestine (J. Bone Min. Res., 7:457-463 (1992)).
The rapid actions of 1.alpha.,25(OH).sub.2 D.sub.3 on the cell membrane seem to regulate cell biological function and interact with other membrane-mediated kinase cascades or to be involved in cross-talk with the cell nucleus to modify genomic responses of cell differentiation and proliferation as described in Norman A. W., et al, Endocrinology, (Feb. 1998).
The family of enzymes known as mitogen activated protein kinase (MAP kinase) belongs to the family of serine/threonine protein kinases which can be activated by phosphorylation of a tyrosine residue induced by mitogens or cell differentiating agents, (Trends Biochem. Sci., 17:233-238 (1992); J. Cell Biol., 12:1079-1088 (1993)). MAP kinase integrates multiple intracellular signals transmitted by various second messengers, (J. Biol. Chem., 270:3642-3647 (1995), and regulates many cellular functions by phosphorylation of several cytoplasmic kinases and nuclear transcription factors including the EGF receptor, c-Myc and c-Jun, (Science, 260:315-319 (1993)).
It has now been discovered that certain analogs of 1.alpha.,25(OH).sub.2 D.sub.3 have biological activities similar to those of 1.alpha.,25(OH).sub.2 D.sub.3 without having, at the same time, undesirable secondary symptoms. Moreover, their biological activities are dependent on their respective chemical structures and these analogs are, therefore, more specific in their biological action. Some of these analogs act both as agonists of slow genomic responses and agonists of rapid responses while the others act solely as agonists or antagonists for rapid nongenomic responses.
It is, therefore, a primary object of this invention to provide specific agonists for generation of regulatory or cellular proteins via regulation of gene expression, that is by slow genomic responses, as well as up or down regulation of these slow genomic responses via agonists or antagonists of the rapid nongenomic responses.
All patents, patent applications and publications cited herein are hereby incorporated by reference.